Vol. 57, Issue 2, 392-400, February 2000

Selective Block of Late Currents in the KPQ Na⁺ Channel Mutant by Pilsicainide and Lidocaine with Distinct Mechanisms

Katsushige Ono,¹ Toshihiko Kaku,¹ Naomasa Makita,² Akira Kitabatake,² and Makoto Arita¹

Department of Physiology, Oita Medical University, Hasama, Oita (K.O., T.K., M.A.); and Department of Cardiovascular Medicine, Hokkaido University School of Medicine, Sapporo, Hokkaido (N.M., A.K.), Japan.

The congenital long QT syndrome is an inherited disorder characterized by a delay in cardiac repolarization, leading to lethal cardiac arrhythmias such as torsade de pointes. One form of this disease involves mutations in the voltage-dependent cardiac Na⁺ channel, which includes an in-frame deletion of three amino acids (Lys-1505, Pro-1506, and Gln-1507; KPQ). The potential for selective suppression of the mutant was examined by heterologous expression of KPQ-Na⁺ channels in Chinese hamster fibroblast cells via single-channel recording. In a single-channel cell-attached patch study, KPQ-Na⁺ channels yielded currents that peaked at ~1 ms after voltage steps to 0 mV with aberrant late currents, which were composed of burst and isolated openings. The affinity of certain anesthetics (pilsicainide and lidocaine) to the late currents of the mutant channels was examined. It was revealed that 1) pilsicainide (1 µM), an open channel blocker of voltage-dependent Na⁺ channels, remarkably decreased the late currents primarily by the shortening of burst duration without suppressing the initial peak current; and 2) lidocaine (1 µM), an inactivated channel blocker, decreased the late currents primarily by the suppression of isolated channel openings. Because the late currents in KPQ mutants are mainly composed of the burst openings, we conclude that pilsicainide is capable of selectively blocking the late currents in the mutant Na⁺ channels that show dominant abnormal burst openings such as in KPQ mutants.